Process for preparing 2-amino-4-(4-fluorphenyl)-6-alkylpyrimidine-5-carboxylate

ABSTRACT

A process for the preparation of a compound of the formula:                    
     wherein the variables are herein below defined.

This is 371 of PCT/EP00/06099, filed on Jun. 30, 2000 that has prioritybenefit of Provisional Application No. 60/185,371, filed on Feb. 28,2000, and Provisional Application No. 60/185,465, filed on Feb. 28,2000, and has priority benefit of European Patent Application00106303.1, filed on Mar. 23, 2000, European Patent Application99120417.3, filed on Oct. 14, 1999, and European Patent Application99113711.8, filed on Jul. 13, 1999.

The present invention relates to a novel process for the preparation ofcompounds of the general formula

in which R, R², R³ and R⁴ have the meaning below.

Compounds of the formula I are important intermediates for thepreparation of pharmaceutically active compounds, for example of HMG-CoA reductase inhibitors. Japanese Patent publication JP-A 06 256318, andWatanabe M. et al., Bioorg. Med. Chem. 1997, Vol. 5, No. 2, 437-444describe processes for the preparation of compounds of the formula I.

The process described in JP-A 06 256318 has the disadvantage that threestages are needed in order to prepare2-amino-4-(4-fluorophenyl)-6-isopropyl-pyrimidine-5-carboxylic acid.

A process for the preparation of ethyl4-(4-fluorophenyl)-6-isopropyl-2-(N-methanesulphonyl-N-methylamino)pyrimidine-5-carboxylatehas been described by Watanabe M. et al., Bioorg. Med. Chem. 1997, Vol.5, No. 2, 437-444. In this process, in the first stagep-fluorobenzaldehyde is converted using ethyl iso-butyrylacetate into anunsaturated ketoester, which is then cyclocondensed in the second stagewith S-methylisothiourea hydrogensulphate and subsequently dehydrated inthe third stage to give the corresponding pyrimidine. In the fourthstage, this is then oxidized using m-chloroperbenzoic acid to give thecorresponding sulphonylpyrimidine, which is then reacted in the fifthstage with methylamine and subsequent treatment with methanesulphonylchloride to give ethyl4-(4-fluoro-phenyl)-6-isopropyl-2-(N-methanesulphonyl-N-methyl-amino)pyrimidine-5-carboxylate.

It is disadvantageous in this process, on the one hand, that manyreaction stages are necessary and, on the other hand, that the desiredproduct is only formed in moderate yield.

The object of the invention was to make available an economical,industrially feasible process for the preparation of compounds of theformula I.

The object of the invention is achieved by the novel process accordingto the process of the invention.

According to the invention, compounds of the general formula

in which

R is hydrogen or a group of the formula —SO₂R¹;

R¹ is C₁₋₆-alkyl;

R² is hydrogen or C₁₋₆-alkyl;

R³ is C₁₋₆-alkyl;

R⁴ is C₁₋₆-alkyl,

are prepared in that, in a first stage, a compound of the generalformula

in which R³ and R⁴ have the abovementioned meaning, is reacted in thepresence of a Lewis acid with 4-fluorobenzonitrile to give a compound ofthe general formula

in which R³ and R⁴ have the abovementioned meaning, and in a secondstage the compound of the formula III obtained is reacted with acompound of the general formula

in which R and R² have the abovementioned meaning, to give the finalproduct of the formula I.

“C₁₋₆-alkyl” is understood here and below as meaning linear and branchedalkyl groups having 1-6 carbon atoms, such as, for example, methyl,ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, sec-butyl, pentyland its isomers and hexyl and its isomers.

The compounds of the formula II can be prepared according to Chem.Berichte 1958, 91, 759 or are commercially available organic syntheticchemicals.

4-Fluorobenzonitrile is a commercially available organic syntheticchemical.

The Lewis acid employed in the first stage is expediently an aproticLewis acid such as, for example, tin tetrachloride, titaniumtetrachloride or aluminium chloride. Tin tetrachloride is preferablyemployed.

The first stage is expediently carried out in the presence of an organicsolvent. The organic solvents employed can be, for example, aromatichydrocarbons, chlorinated aromatic and aliphatic hydrocarbons. Aromatichydrocarbons employed are preferably toluene, benzene or xylene. Thechlorinated aromatic hydrocarbon employed is preferably chlorobenzene;the chlorinated aliphatic hydrocarbon employed is preferably1,2-dichloroethane. Toluene and 1,2-dichloroethane are particularlypreferably employed.

The reaction in the first stage is expediently carried out at atemperature from −5 to 140° C., advantageously at 60 to 100° C.

After a reaction time of 30 min to 6 h and subsequent hydrolysis, thecompounds of the formula III can be isolated by known methods such as,for example, by extraction or can be employed directly, withoutisolation, for the second stage. The intermediate (formula III) ispreferably isolated.

Compounds of the formula III include cis and trans isomers.

In a second stage, a compound of the formula III is reacted with acompound of the formula IV to give the final product of the formula I.

The invention comprises, on the one hand, compounds of the formula I inwhich R and R² are hydrogen. These compounds are prepared by reaction ofcompounds of the formula III with cyanamide.

The reaction with cyanamide is expediently carried out in the presenceof an organic solvent, a mixture of water with an organic solvent or inwater. Water is particularly preferably employed. Organic solventsemployed are advantageously toluene or ethyl acetate. Organic solventsemployed as a mixture with water are advantageously alcohols such as,for example, methanol, ethers such as, for example, dioxane or aromatichydrocarbons such as, for example, toluene or N,N-dimethylacetamide.

The reaction with cyanamide is expediently carried out at a temperatureof 10 to 120° C., advantageously at 40 to 100° C. The pH is expedientlyin a range from 3 to 9, advantageously in a range from 4 to 7. After areaction time of, in total, 1 to 20 h, the compounds of the generalformula I are obtained, which can be worked up according to knownmethods.

In a particular embodiment,2-amino-4-(4-fluorophenyl)-6-isopropylpyrimidine-5-carboxylic acidesters of the general formula

in which R³ has the meaning indicated in formula I are prepared in that,in a first stage, an alkyl iso-butyrylacetate of the general formula

in which R³ has the meaning mentioned is reacted in the presence of aLewis acid with 4-fluorobenzonitrile to give a2-[1-amino-1-(4-fluorophenyl)methylene]-4-methyl-3-oxopentanoic acidester of the general formula

and in a second stage the compound of the formula IIIa is reacted withcyanamide of the formula

in which R and R² are hydrogen, to give the final product of the formulaIa.

The radical R³ is preferably methyl.

The compounds of the formula III are novel and also a subject of theinvention.

The invention comprises, on the other hand, compounds of the formula Iin which R is a group of the formula —SO₂R¹ and R¹ and R² areC₁₋₆-alkyl. These4-(4-fluorophenyl)-6-alkyl-2-(N-alkanesulphonyl-N-alkylamino)pyrimidine-5-carboxylicacid esters of the general formula

in which R¹, R², R³ and R⁴ are identical or different and are aC₁₋₆-alkyl group, can be prepared in that2-[1-amino-1-(4-fluorophenyl)methylene]-4-alkyl-3-oxo-alkanoic acidesters of the general formula

in which R³ and R⁴ have the abovementioned meaning, are reacted withN-cyano-N-alkylalkanesulphonamides, optionally isolated or prepared insitu, of the general formula

in which R¹ and R² are a C₁₋₆-alkyl group.

The reaction can be carried out either in the presence of a base or inthe presence of a Lewis acid.

Bases which can be employed are alkali metal compounds such as, forexample, alkali metal hydrides, alkali metal carbonates, alkali metalalkoxides or alkali metal silazanes. Alkali metal carbonates which canbe used are lithium, sodium or potassium carbonate. The alkali metalhydride employed can be potassium, lithium or sodium hydride; sodiumhydride is preferably employed. The alkali metal alkoxide employed canbe sodium or potassium tert-pentoxide or sodium or potassiumtert-butoxide, preferably sodium tert-pentoxide or sodium tert-butoxide.The alkali metal silazane used can be sodium hexamethyldisilazane orpotassium hexamethyldisilazane. The base preferably employed is analkali metal hydride or an alkali metal alkoxide.

The reaction is expediently carried out in the presence of a base in apolar organic solvent. The polar solvent used can be, for example,N,N-dimethyl-acetamide, isopropanol, tert-butanol, toluene,di-methylformamide, tetrahydrofuran, 1,4-dioxane or mixtures of these.N-Alkylalkanesulphonamides such as, for example,N-methylmethanesulphonamide are likewise suitable as solvents. Thereaction is preferably carried out in N-alkylalkanesulphonamide andtert-butanol.

The reaction can be carried out in the presence of a base at atemperature from −10 to 150° C., preferably from 0 to 80° C.

The reaction of compounds of the formula IIIb with compounds of theformula IVb in the presence of a Lewis acid is expediently carried outin the solvent which is inert to the Lewis acid. Inert solvents whichcan be employed are, for example, aromatic hydrocarbons, and chlorinatedaromatic and aliphatic hydrocarbons. Aromatic hydrocarbons employed arepreferably toluene or xylene. The chlorinated aromatic hydrocarbonemployed is preferably chlorobenzene; chlorinated aliphatic hydrocarbonsemployed are preferably dichloromethane or 1,2-dichloroethane.

The reaction in the presence of a Lewis acid can be carried out at atemperature from 20 to 150° C., preferably from 80 to 120° C.

Suitable Lewis acids are for example TiCl₄, TiBr₄ or SnCl₄. Titaniumtetrachloride is preferred.

The amount of Lewis acid is 0.1 to 2 molar equivalents based on thecompound of the formula IIIb.

After a reaction time of 1 to 24 h, the final products of the generalformula Ib can be isolated by known working-up methods.

In a preferred embodiment, the final product of the formula Ib isolatedis ethyl4-(4-fluorophenyl)-6-isopropyl-2-(N-methanesulphonyl-N-methylamino)-pyrimidine-5-carboxylate(R¹=R²=R³=methyl, R⁴=isopropyl).

Compounds of the formula IVb are expediently prepared in that a compoundof the general formula

in which R¹ and R² are C₁₋₆-alkyl, is reacted with cyanogen halide inthe presence of a base.

Suitable bases are the bases described beforehand.

The cyanogen halide employed can be cyanogen fluoride, cyanogenchloride, cyanogen bromide or cyanogen iodide. Cyanogen chloride orcyanogen bromide is preferably employed.

This reaction can likewise be carried out in the polar organic solventsdescribed beforehand. The reaction is preferably carried out intetrahydrofuran.

The reaction is expediently carried out at a temperature from −20 to 50°C., preferably at a temperature from −10 to +20° C.

After a reaction time of ¾ to 1 h, the compounds of the formula IVb,which have not yet been described in the literature, can then beisolated in a manner known to the person skilled in the art.

These compounds of the formula IVb are also a subject of the invention.

Compounds of the formula IVb can be prepared in situ, i.e. they areformed directly from the corresponding starting materials during thereaction without isolation. However, they can also be prepared andisolated separately in order then to employ them for the reaction.

Examples of compounds of the formula IVb are:N-cyano-N-methylmethanesulphonamide,N-cyano-N-ethyl-methanesulphonamide,N-cyano-N-propylmethanesulphonamide, N-cyano-N-butylmethanesulphonamide,N-cyano-N-pentylmethanesulphonamide andN-cyano-N-hexylmethanesulphonamide. N-Cyano-N-methylmethanesulphonamideis preferred.

The compounds of the formula I can also be prepared in that a compoundof the general formula

in which R³ and R⁴ have the meaning mentioned in claim 1, is reactedwith a compound of the formula IV.

The reaction is carried out analogously to the reaction of the compoundsof the formula III with compounds of the formula IV, preferably in thepresence of a base in a polar organic solvent at a temperature from −10to 150° C.

Suitable bases and solvents correspond to the bases and solvents whichare listed under the reaction of compounds of the formula III withcompounds of the formula IV.

In a preferred embodiment, compounds of the general formula Ib areprepared in that a compound of the formula VI is reacted with a compoundof the formula IVb in a polar organic solvent at a temperature from 0 to80° C. in the presence of a base.

The compounds of the formula VI can be prepared by reaction ofC₁₋₆-alkyl nitriles with C₁₋₆-alkyl 4-fluorobenzoylacetate in thepresence of a Lewis acid. A compound of the formula VI in which R³ ismethyl and R⁴ is isopropyl is preferred. The Lewis acid is preferablytin tetrachloride. The reaction is expediently carried out in a polarsolvent. Suitable solvents correspond to the solvents which are listedunder the reaction of compounds of the formula II with compounds of theformula III described above. The reaction in the first stage isexpediently carried out at a temperature from −5 to 140° C.,advantageously at 60 to 100° C.

The compounds of the formula VI are novel and likewise a subject of theinvention.

EXAMPLES Example 1 Methyl2-[1-amino-1-(4-fluorophenyl)methylene]-4-methyl-3-oxopentanoate

IIIa, R³=Methyl, Toluene, SnCl₄

1.50 g of methyl isobutyrylacetate (10.0 mmol, concentration 96%) and1.24 g of 4-fluorobenzonitrile (10 mmol, concentration 98%) weredissolved in 10 ml of toluene and treated with 2.63 g of tintetrachloride (10 mmol, concentration 99%) at room temperature over thecourse of 6 min. After 3 h at room temperature, the mixture was heatedto 80° C. After 2.5 h, the suspension was again cooled to roomtemperature and treated with 10 ml of water. It was diluted with 5 ml ofethyl acetate and the phases were separated. After extraction of theaqueous phase with ethyl acetate (2×5 ml), the combined organic phaseswere dried over magnesium sulphate. After concentration in vacuo, 3.50 gof crude product were obtained in the form of a pale yellow, tackysolid. The solid was dissolved in ethyl acetate and purified by flashchromatography (n-hexane/ethyl acetate 5:1 to 1:1). After concentrationin vacuo, 1.44 g of methyl2-[1-amino-1-(4-fluorophenyl)-methylene]-4-methyl-3-oxopentanoate wereobtained.

Yield: 54.3% (concentration >99%) in the form of a colourless solid.

Melting point: 85.8-86.6° C.

Example 2 Methyl2-[1-amino-1-(4-fluorophenyl)methylene]-4-methyl-3-oxopentanoate

IIIa, R³=Methyl, Toluene, SnCl₄

22.53 g of methyl isobutyrylacetate (0.15 mol, concentration 96%) and18.54 g of 4-fluorobenzonitrile (0.15 mol, concentration 98%) weredissolved in 150 ml of toluene and treated with 43.32 g of tintetrachloride (0.165 mol, concentration 99%) at room temperature overthe course of 12 min. After half an hour at room temperature, themixture was heated to 80° C. After 3 h, the suspension was cooled toroom temperature and treated with 150 ml of water. It was diluted with100 ml of ethyl acetate and the phases were separated. After extractionof the aqueous phase with ethyl acetate (2×100 ml), the combined organicphases were washed with 100 ml of saturated aqueous sodiumhydrogencarbonate solution and 100 ml of 1N sodium hydroxide solutionand dried over magnesium sulphate. After concentration in vacuo, 46.46 gof crude product were obtained in the form of a yellowish solid. Thesolid was dissolved in a mixture of 50 ml of n-hexane and 5 ml oftoluene under reflux and filtered hot. The product precipitated from thefiltrate on cooling. By filtering through a frit and washing the filtercake with 2×40 ml of n-hexane, 32.42 g of methyl2-[1-amino-1-(4-fluorophenyl)methylene]-4-methyl-3-oxopentanoate wereobtained in the form of a spectroscopically pure solid.

Yield: 80.7% (concentration 99.0%)

Melting point: 84.0-84.9° C.

¹H NMR (DMSO-d⁶, 400 MHz): δ=0.98 (d, 6H); 3.06 (sept, 1H); 3.24 (s,3H); 7.27 (t, 2H); 7.35 (m, 2H); 8.38 (s, 1H); 10.59 (s, 1H).

¹³C NMR (DMSO-d⁶, 100 MHz): δ=19.45 (q); 36.04 (d); 50.74 (q); 101.54(s); 115.11 (sd); 115.33 (sd); 129.16 (dd); 129.25 (dd); 133.68 (sd);161.46.54 (s); 163.91 (s); 165.59 (s); 169.71 (s); 201.10 (s).

Example 3 Methyl2-[1-amino-1-(4-fluorophenyl)methylene]-4-methyl-3-oxopentanoate

IIIa, R³=Methyl, Toluene, SnCl₄

75.09 g of methyl isobutyrylacetate (0.50 mol, concentration 96%) and61.80 g of 4-fluorobenzonitrile (0.50 mol, concentration 98%) wereintroduced into [500 ml of toluene and treated with 144.7 g of tintetrachloride (0.55 mol, concentration 99%) at room temperature over thecourse of 16 min. After half an hour at room temperature, the thicksuspension was heated to 80° C. After 3 h, 175 ml of toluene weredistilled off at normal pressure, and the mixture was cooled to roomtemperature and treated with 450 ml of saturated sodium carbonate and300 ml of ethyl acetate. The organic phase was separated off and theaqueous phase (after dilution with 300 ml of water) was again extractedwith 300 ml of ethyl acetate. After drying the combined organic phasesover sodium sulphate, the solvent was removed in vacuo (40° C./25 mbar).127.2 g of crude product were obtained in the form of a slightlyyellowish solid, which was dissolved in 160 ml of n-hexane (slightlyturbid solution). After hot filtration and subsequent cooling in an icebath, 99.8 g of methyl2-[1-amino-1-(4-fluorophenyl)-methylene]-4-methyl-3-oxopentanoate wereobtained after filtration in the form of a pale yellow solid.

Yield: 74.5% (concentration 99.3%)

Melting point: 86.4-87.8° C.

Example 4 Methyl2-[1-amino-1-(4-fluorophenyl)methylene]-4-methyl-3-oxopentanoate

IIIa, R³=Methyl, 1,2-dichloroethane, AlCl₃

754 mg of methyl isobutyrylacetate (5.00 mmol, concentration 96%) and618 mg of 4-fluorobenzonitrile (5.00 mmol, concentration 98%) wereintroduced into 5 ml of 1,2-dichloroethane and treated with 673 mg ofaluminium chloride (5.00 mol) at room temperature. After one hour atroom temperature, the mixture was heated to 80° C. After 19 h—themixture contained 13.9 area per cent of product according to HPLCanalysis—the mixture was cooled to room temperature and treated withwater (5 ml). The organic phase was separated off and the aqueous phasewas extracted with dichloromethane (3×5 ml). The combined organic phaseswere dried over magnesium sulphate and concentrated in vacuo. 1.01 g ofcrude product were obtained, which contained 3% (30 mg) of methyl2-[1-amino-1-(4-fluorophenyl)methylene]-4-methyl-3-oxopentanoateaccording to ¹H-NMR spectrum.

Example 5 Methyl2-[1-amino-1-(4-fluorophenyl)methylene]-4-methyl-3-oxopentanoate

IIIa, R³=Methyl, Toluene, SnCl₄

75.09 g of methyl isobutyrylacetate (0.50 mol, concentration 96%) and61.8 g of 4-fluorobenzonitrile (0.50 mol, concentration 98%) weredissolved in 500 ml of toluene and treated with 144.72 g of tintetrachloride (0.55 mol, concentration 99%) at room temperature over thecourse of 15 min. After half an hour at room temperature, the mixturewas heated to 80° C. After 3 h, the suspension was cooled to 10° C. andtreated with 500 ml of water. The mixture was diluted with 100 ml ofdichloroethane and the phases were separated. The organic phase waswashed with 2×100 ml of 1N sodium hydroxide solution. Afterconcentration in vacuo, 125.5 g of crude product were obtained in theform of a yellowish solid. The solid was dissolved in 160 ml of n-hexaneunder reflux and filtered hot. The product precipitated from thefiltrate on cooling. By filtering through a frit and washing the filtercake with 130 ml of n-hexane, 79.8 g of methyl2-[1-amino-1-(4-fluorophenyl)methylene]-4-methyl-3-oxopentanoate wereobtained in the form of a spectroscopically pure solid.

Yield: 60.7% (concentration 98.7%)

Melting point: 88.4-89.3° C.

Example 6 Methyl2-amino-4-(4-fluorophenyl)-6-isopropylpyrimidine-5-carboxylate

Ia, R³=Methyl, Water

A suspension of 1.33 g of methyl2-[1-amino-1-(4-fluorophenyl)methylene]-4-methyl-3-oxopentanoate (5.00mmol) in 4.20 g of 50% strength aqueous cyanamide solution (50.0 mmol)was heated to reflux. After 17 h, it was cooled to room temperature andtreated with ethyl acetate (5 ml) and water (5 ml). The undissolvedsolid was filtered off. The organic phase was separated off and theaqueous phase was extracted with ethyl acetate (2×5 ml). The combinedorganic phases were dried over magnesium sulphate and concentrated invacuo. The crude product (0.97 g) was purified by flash chromatographyon silica gel (eluent: methylene chloride). 121.6 mg of methyl2-amino-4-(4-fluorophenyl)-6-isopropylpyrimidine-5-carboxylate wereobtained in the form of a colourless solid.

Yield: 8.4%

Melting point: 146.2-147.0° C.

¹H NMR (DMSO-d⁶ ₁, 400 MHz): δ=1.08 (d, 6H); 3.04 (sept, 1H); 3.57 (s,3H); 7.05 (s, broad, 2H); 7.28 (m, 2H); 7.53 (m, 2H).

Example 7 Methyl2-amino-4-(4-fluorophenyl)-6-isopropylpyrimidine-5-carboxylate

Ia, R³=Methyl, N,N-dimethylacetamide

5.00 g of methyl2-[1-amino-1-(4-fluorophenyl)-methylene]-4-methyl-3-oxopentanoate (18.7mmol) were treated with 5 ml of N-N-dimethylacetamide and 15.71 g of a50% strength aqueous cyanamide solution (187 mmol) and heated to reflux.After 5 h, the solution was poured onto 50 ml of water. The mixture wascooled in an ice bath and the deposited precipitate was isolated bymeans of a suction filter. After drying, 2.72 g of crude product wereobtained in the form of a yellowish solid. After flash chromatography(150 g of silica gel; eluent: hexane/ethyl acetate 3:2), 1.19 g ofmethyl 2-amino-4-(4-fluorophenyl)-6-isopropylpyrimidine-5-carboxylatewere isolated in the form of a colourless solid.

Yield: 22.0%

Melting point: 145-146° C.

Example 8 N-Cyano-N-methylmethanesulphonamide

IVb, R¹=R²=Methyl

12.22 g (0.28 mol) of sodium hydride (55% in oil) were twice suspendedin 100 ml of n-hexane under nitrogen and freed from the oil by means ofa frit. The hexane-moist sodium hydride was taken up in 200 ml oftetrahydrofuran and cautiously treated at 2° C. with 22.98 g (0.20 mol)of N-methylmethanesulphonamide (concentration 95%). Evolution of gas wasobserved. After addition was complete (25 min), the cooling bath wasremoved and the mixture was subsequently reacted at room temperature for3 h 40 min until evolution of hydrogen was no longer observed. Themixture was subsequently cooled again using an ice bath and 20.0 g (0.32mol) of cyanogen chloride (concentration 99%) were cautiously introducedover the course of 40 min (slightly exothermic). After subsequentreaction at 0-5° C. for 45 min, the reaction mixture was poured onto 200ml of ice water. The phases were separated and the aqueous phase wasextracted with 1×200 ml and two times 100 ml of diethyl ether. Theorganic phases were combined and dried over magnesium sulphate. Afterfiltration and concentration in vacuo, 26.57 g of crude product wereobtained in the form of a yellowish, two-phase oil, which partiallycrystallized in the refrigerator. After distillation in vacuo (boilingpoint 90-95° C./0.01 mbar), 17.24 g ofN-cyano-N-methylmethanesulphonamide were obtained in the form of acolourless oil, which crystallized in the refrigerator.

Yield: 61.7%, [concentration: 96.0% (GC)]

Melting point: 29-30° C.

Example 9 N-Cyano-N-methylmethanesulphonamide

IVb, R¹=R²=Methyl

36.65 g (0.84 mol) of sodium hydride (55% in oil) were suspended threetimes in 200 ml of n-hexane under nitrogen and freed from the oil bymeans of a frit. The hexane-moist sodium hydride was taken up in 600 mlof tetrahydrofuran and cautiously treated at 2° C. with 68.94 g (0.60mol) of N-methylmethanesulphonamide (concentration 95%). Evolution ofgas was observed. After addition was complete (45 min), the cooling bathwas removed and the mixture was subsequently reacted at room temperaturefor 4 h 25 min until evolution of hydrogen was no longer observed. Itwas subsequently cooled again using an ice bath and 59.6 g (0.96 mol) ofcyanogen chloride (concentration 99%) were cautiously introduced overthe course of 1 h 45 min (slightly exothermic). After subsequentreaction at 0-5° C. for 20 min, the reaction mixture was poured onto 600ml of ice water. The phases were separated and the aqueous phase wasextracted with 2×500 ml of diethyl ether. The combined organic phaseswere dried over magnesium sulphate. After filtration and concentrationin vacuo, 99.22 g of crude product were obtained, which crystallized at15° C. After filtration, 70.56 g of crude product were isolated in theform of a tacky, colourless solid. After distillation in vacuo (boilingpoint 90-95° C./0.01 mbar), 57.4 g ofN-cyano-N-methyl-methanesulphonamide were obtained in the form of acolourless oil, which crystallized in the refrigerator.

Yield: 71.3%, [concentration: >99% (GC)]

Melting point: 29.0-30.0° C.

¹H NMR (DMSO-d⁶, 400 MHz): δ=3.28 (s, 3H); 3.48 (s, 3H).

¹³C NMR (DMSO-d⁶, 100 MHz): δ=35.46 (q); 37.74 (q); 109.35 (s).

Example 10 N-Cyano-N-methylmethanesulphonamide

IVb, R¹=R²=Methyl

36.7 g (0.84 mol) of sodium hydride (55% in oil) were suspended threetimes in 200 ml of n-hexane under nitrogen and freed from the oil bymeans of a frit. The hexane-moist sodium hydride was taken up in 600 mlof tetrahydrofuran and cautiously treated at 2° C. with 68.94 g (0.60mol) of N-methylmethanesulphonamide (concentration 95%). Evolution ofgas was observed. After addition was complete (30 min), the cooling bathwas removed and the mixture was subsequently reacted at room temperaturefor 4 h until evolution of hydrogen was no longer observed. It wassubsequently cooled again using an ice bath and 59.6 g (0.96 mol) ofcyanogen chloride (concentration 99%) were cautiously introduced overthe course of 2 h (slightly exothermic). After subsequent reaction at0-5° C. for 20 min, the reaction mixture was poured onto 600 ml of icewater. After addition of 500 ml of diethyl ether, the phases wereseparated and the aqueous phase was extracted with 500 ml of diethylether. The combined organic phases were dried over magnesium sulphate.After filtration and concentration in vacuo, 99.22 g of crude productwere obtained, which crystallized at 15° C. After filtration, 86.5 g ofcrude product were isolated in the form of a tacky, colourless solid.After distillation in vacuo (boiling point 91-93° C./0.1 mbar), 72.9 gof N-cyano-N-methylmethanesulphonamide were obtained in the form of acolourless oil which crystallized in the refrigerator.

Yield: 90.6%, [concentration: >99% (GC)]

Example 11 Methyl4-(4-fluorophenyl)-6-isopropyl-2-(N-methanesulphonyl-N-methylamino)pyrimidine-5-carboxylate

Ib, R¹=R²=R³=Methyl, R⁴=Isopropyl, NaH

2.66 g (10.0 mmol) of methyl2-[1-amino-1-(4-fluorophenyl)methylene]-4-methyl-3-oxopentanoate wereintroduced into 12 g of N,N-dimethylacetamide together with 2.70 g (20.0mmol) of N-cyano-N-methylmethanesulphonamide. 440 mg (11.0 mmol) ofsodium hydride (60% in oil) were added to this solution at roomtemperature over the course of 2 h. An orange-red clear solution wasobtained. After 6 h at room temperature, the reaction solution waspoured onto 25 ml of water. The suspension was stirred in an ice bathfor 30 minutes, and the precipitate was filtered off and washed withwater (2×10 ml). After drying in a high vacuum, 1.11 g (29.1%) of methyl4-(4-fluorophenyl)-6-isopropyl-2-(N-methanesulphonyl-N-methylamino)pyrimidine-5-carboxylatewere obtained in the form of a pale beige solid. The product stillcontained traces of methyl2-[1-amino-1-(4-fluorophenyl)methylene]-4-methyl-3-oxopentanoate.

¹H NMR (DMSO-d⁶, 400 MHz): δ=1.15 (d, 6H); 3.17 (sept, 1H); 3.50 (s,3H); 3.58 (s, 3H); 3.73 (s, 3H); 7.39 (m, 2H); 7.69 (m, 2H).

Example 12 Methyl4-(4-fluorophenyl)-6-isopropyl-2-(N-methanesulphonyl-N-methylamino)pyrimidine-5-carboxylate

Ib, R¹=R²=R³=Methyl, R⁴=Isopropyl, Sodium Tert-pentoxide

2.66 g (10.0 mmol) of methyl2-[1-amino-1-(4-fluorophenyl)methylene]-4-methyl-3-oxopentanoate wereintroduced into 7 g of N,N-dimethylacetamide together with 2.70 g (20.0mmol) of N-cyano-N-methylmethanesulphonamide. 1.21 g (11.0 mmol) ofsodium tert-pentoxide in 5 g of dimethylacetamide were added to thissolution at room temperature after the course of 3 h. An orange-redclear solution was obtained. After 2.5 h at room temperature, thereaction solution was poured onto 25 ml of water. The suspension wasstirred in an ice bath for 30 minutes, and the precipitate was filteredoff and washed with water (10 ml). After drying in a high vacuum, 1.65 gof crude product were obtained in the form of a pale beige solid whichcontained 676.5 mg of methyl4-(4-fluorophenyl)-6-isopropyl-2-(N-methanesulphonyl-N-methylamino)-pyrimidine-5-carboxylate.

Yield: 17.7%

Example 13 Methyl4-(4-fluorophenyl)-6-isopropyl-2-(N-methanesulphonyl-N-methylamino)pyrimidine-5-carboxylate

Ib, R¹=R²=R³=Methyl, R⁴=Isopropyl, NaH

10.0 g (37.7 mmol) of methyl2-[1-amino-1-(4-fluorophenyl)methylene]-4-methyl-3-oxopentanoate wereintroduced into 45 ml of N,N-dimethylacetamide together with 15.2 g (113mmol) of N-cyano-N-methylmethanesulphonamide. 3.50 g (88.7 mmol) ofsodium hydride (60% in oil) were added at room temperature to thissolution. An orange-red viscous solution was obtained. The reactionsolution was poured onto 120 ml of water and stirred in an ice bath for30 minutes. The precipitate was filtered off and washed with water (10ml). After drying in a high vacuum, 4.60 g of crude product wereobtained in the form of a pale beige solid. According to the ¹H NMRspectrum, the solid contained an 84:16 product/starting materialmixture, which corresponds to a yield of 27% of methyl4-(4-fluorophenyl)-6-isopropyl-2-(N-methanesulphonyl-N-methylamino)pyrimidine-5-carboxylate.

Example 14 Methyl4-(4-fluorophenyl)-6-isopropyl-2-(N-methanesulphonyl-N-methylamino)pyrimidine-5-carboxylate

Ib, R¹=R²=R³=Methyl, R⁴=Isopropyl, NaH, Compound of the Formula IVbFormed in situ

2.65 g (10.0 mmol) of methyl2-[1-amino-1-(4-fluorophenyl)methylene]-4-methyl-3-oxopentanoate wereintroduced into 5 g of N-N-dimethylacetamide together with 2.30 g (20.0mmol) of N-methylmethanesulphonamide. 470 mg (20.0 mmol) of sodiumhydride (60% in oil) were added to this solution at room temperature.The reaction solution was treated with 2.40 g (40.0 mmol) of cyanogenchloride at room temperature. After 20 h, the mixture was poured onto 40ml of water and the yellowish suspension was cooled in an ice bath. Theprecipitate deposited was filtered off and washed with 20 ml of water.After drying in vacuo, 2.22 g of crude product were obtained in the formof a pale beige solid, which according to the ¹H NMR spectrum containeda 70:30 starting material/product mixture, which corresponds to a yieldof 22% of methyl4-(4-fluorophenyl)-6-isopropyl-2-(N-methanesulphonyl-N-methylamino)pyrimidine-5-carboxylate.

Example 15 Methyl4-(4-fluorophenyl)-6-isopropyl-2-(N-methanesulphonyl-N-methylamino)pyrimidine-5-carboxylate

Ib, R¹=R²=R³=Methyl, R⁴=Isopropyl, NaH, Compound of the Formula IVbFormed in situ

13.3 g (50.0 mmol) of methyl2-[1-amino-1-(4-fluorophenyl)methylene]-4-methyl-3-oxopentanoate wereintroduced into 25 g of N,N-dimethylacetamide together with 10.9 g(100.0 mmol) of N-methylmethanesulphonamide. 3.60 g (90.0 mmol) ofsodium hydride (60% in oil) were added to this solution at 25° C.Vigorous foaming was observed. After 15 min at 25° C., 6.0 g (100.0mmol) of cyanogen chloride gas were introduced after the course of 20min. An orange-coloured suspension was formed. This was stirred at 25°C. for 2 h and 2.40 g (60.0 mmol) of sodium hydride (60% in oil) andsubsequently 6.0 g (100.0 mmol) of cyanogen chloride were added again.The mixture was stirred at 25° C. again for 1 h before a further 3.60 g(90.0 mmol) of sodium hydride (60% in oil) were added. The reactionmixture was poured onto an ice/water mixture (200 ml) and stirred at 0°C. for 1 h. The resulting solid was filtered off and washed with 100 mlof water. After drying in a high vacuum, 14.62 g of crude product wereobtained in the form of a beige solid. 8.22 g of this solid wererecrystallized in an acetone/water mixture. 4.24 g of product wereobtained in the form of a pale beige solid, which corresponds to a yieldof 29% [concentration (GC) 72%].

Example 16 Methyl4-(4-fluorophenyl)-6-isopropyl-2-(N-methanesulphonyl-N-methylamino)pyrimidine-5-carboxylate

Ib, R¹=R²=R³=Methyl, R⁴=Isopropyl, NaH, Compound of the Formula IVbFormed in situ

13.3 g (50.0 mmol) of methyl2-[1-amino-1-(4-fluorophenyl)methylene]-4-methyl-3-oxopentanoate wereintroduced into 25 g of N,N-dimethylacetamide together with 10.9 g(100.0 mmol) of N-methylmethanesulphonamide. 3.60 g (90.0 mmol) ofsodium hydride (60% in oil) were added to this solution at 25° C.Vigorous foaming was observed. After 25 min at 25° C., 6.0 g (100.0mmol) of cyanogen chloride gas were introduced after the course of 12min. During this, the temperature rose temporarily to 32° C. Anorange-coloured suspension was formed. The mixture was stirred at 25° C.for 1 h 25 min and 2.40 g (60.0 mmol) of sodium hydride (60% in oil) andsubsequently 3.0 g (50.0 mmol) of cyanogen chloride were added again.The mixture was stirred at 25° C. again for 1 h 40 min before a further2.40 g (60.0 mmol) of sodium hydride (60% in oil) and 3.0 g (50.0 mmol)of cyanogen chloride were added. After addition of a further 2.40 g(60.0 mmol) of sodium hydride (60% in oil), the reaction mixture waspoured onto an ice/water mixture (200 ml). The apparatus was washed with50 ml of water and tie mixture was stirred at 0° C. for 1 h. Theresulting solid was filtered off and washed with 50 ml of water. Afterdrying in a high vacuum, 10.47 g of crude product were obtained in theform of a beige solid. 8.00 g of this solid were recrystallized in anacetone/water mixture. 5.50 g of product were obtained in the form of apale beige solid, which corresponded to a yield of 30.2% [concentration(GC) 80%].

Example 17 Methyl4-(4-fluorophenyl)-6-isopropyl-2-(N-methanesulphonyl-N-methylamino)pyrimidine-5-carboxylate

Ib, R¹=R²=R³=Methyl, R⁴=Isopropyl, NaH, Compound of the Formula IVbFormed in situ

13.3 g (50.0 mmol) of methyl2-[1-amino-1-(4-fluorophenyl)methylene]-4-methyl-3-oxopentanoate wereintroduced into 50.0 g (0.46 mol) of N-methyl-methanesulphonamide. 12.0g (0.30 mol) of sodium hydride (60% in oil) were added to this solutionat 25° C. after the course of 1 h 45 min. Vigorous foaming was observed.In order to guarantee better stirrability, 30.0 g (0.275 mol) ofN-methyl-methane-sulphonamide were added again during the addition.After 30 min at 25° C., 15.0 g (0.25 mol) of cyanogen chloride gas wereintroduced over the course of 50 min. The suspension was transferred toan autoclave and stirred at 60° C. for 18.5 h. The reaction mixture waspoured onto an ice/water mixture (200 ml) and stirred at 0° C. for 30min. The resulting solid was filtered off and washed with 50 ml ofwater. After drying in a high vacuum, 18.71 g of crude product wereobtained in the form of a beige solid. 10.0 g of this solid wererecrystallized in an acetone/water mixture. 5.40 g of methyl4-(4-fluorophenyl)-6-isopropyl-2-(N-methanesulphonyl-N-methylamino)pyrimidine-5-carboxylatewere obtained in the form of a colourless solid.

Yield of 50.6%, [concentration 95.5% (GC)].

Example 18 Methyl4-(4-fluorophenyl)-6-isopropyl-2-(N-methanesulphonyl-N-methylamino)pyrimidine-5-carboxylate

Ib, R¹=R²=R³=Methyl, R⁴=Isopropyl, Sodium Tert-pentoxide, Compound ofthe Formula IVb Formed in situ

13.3 g (50.0 mmol) of methyl2-[1-amino-1-(4-fluorophenyl)methylene]-4-methyl-3-oxopentanoate wereintroduced into 50.0 g (0:46 mol) of N-methylmethanesulphonamide. 33.0 g(0.30 mol) of sodium tert-pentoxide were added to this solution at 25°C. after the course of 20 min. A yellowish, thick suspension was formed.After 30 min at 25° C., 15.0 g (0.25 mmol) of cyanogen chloride gas wereintroduced after the course of 25 min. The suspension, which was nowmore readily stirrable, was transferred to an autoclave and stirred at60° C. for 17 h. The reaction mixture was poured onto an ice/watermixture (200 ml) and stirred at 0° C. for 30 min. The resulting solidwas filtered off and washed with 50 ml of water. After drying in a highvacuum, 20.81 g of crude product were obtained in the form of a beigesolid having a concentration of about 68% (GC). This corresponded to ayield of 74.1% of methyl4-(4-fluorophenyl)-6-isopropyl-2-(N-methanesulphonyl-N-methylamino)pyrimidine-5-carboxylate.

EXAMPLE 19 Methyl4-(4-fluorophenyl)-6-isopropyl-2-(N-methanesulphonyl-N-methylamino)pyrimidine-5-carboxylate

Ib, R¹=R²=R³=Methyl, R⁴=Isopropyl, TiCl₄, Chlorobenzene

10.0 g (37.7 mmol) of methyl2-[1-amino-1-(4-fluorophenyl)methylene]-4-methyl-3-oxopentanoate wereintroduced into 50 ml of chlorobenzene together with 10.17 g (75.4 mmol)of N-cyano-N-methylmethanesulphonamide and the mixture was treated atroom temperature with 7.22 g (37.7 mmol) of titanium tetrachloride. Thereaction progressed exothermically. The red-orange-coloured suspensionwas heated to 110-120° C. and stirred for 3.5 h. It was then cooled toroom temperature and treated with 30 ml of water. The organic phase wasseparated off and the aqueous phase was extracted with methylenechloride (30 ml). The combined organic phases were washed with 30 ml ofwater and dried over magnesium sulphate. After filtering andconcentrating the solution in a water-jet vacuum and drying in vacuo,11.48 g of crude product were obtained in the form of a tacky solid.

Yield: 37.8% [concentration (HPLC) 47.3%].

Example 20 Methyl4-(4-fluorophenyl)-6-isopropyl-2-(N-methanesulphonyl-N-methylamino)pyrimidine-5-carboxylate

Ib, R¹=R²=R³=Methyl, R⁴=Isopropyl, TiCl₄, Chlorobenzene

10.0 g (37.7 mmol) of methyl2-[1-amino-1-(4-fluorophenyl)methylene]-4-methyl-3-oxopentanoate wereintroduced into 50 ml of chlorobenzene together with 10.17 g (75.4 mmol)of N-cyano-N-methylmethanesulphonamide and the mixture was treated atroom temperature with 14.45 g (75.4 mmol) of titanium tetrachloride. Thereaction progressed exothermically. The red-orange-coloured suspensionwas heated to 110° C. and stirred for 17.5 h. It was then cooled to roomtemperature and treated with 30 ml of water. The organic phase wasseparated off and the aqueous phase was extracted with methylenechloride (2×30 ml). The combined organic phases were washed with 30 mlof water and dried over magnesium sulphate. After filtering andconcentrating the solution in a water-jet vacuum and drying in vacuo,12.92 g of crude product were obtained in the form of a brownish oil.

Yield: 23.3% [concentration (HPLC) 25.9%].

Example 21 Methyl4-(4-fluorophenyl)-6-isopropyl-2-(N-methanesulphonyl-N-methylamino)pyrimidine-5-carboxylate

Ib, R¹=R²=R³=Methyl, R⁴=Isopropyl, TiCl₄, Toluene

10.0 g (37.7 mmol) of methyl2-[1-amino-1-(4-fluorophenyl)methylene]-4-methyl-3-oxopentanoate wereintroduced into 50 ml of toluene together with 10.17 g (75.4 mmol) ofN-cyano-N-methylmethanesulphonamide and the mixture was treated at roomtemperature with 3.61 g (18.9 mmol) of titanium tetrachloride. Thereaction progressed exothermically. The red-orange-coloured suspensionwas heated to 110° C. and stirred for 4.5 h. It was then cooled to roomtemperature and treated with 30 ml of water. The organic phase wasseparated off and the aqueous phase was extracted with ethyl acetate (30ml). The combined organic phases were washed with 30 ml of water anddried over magnesium sulphate. After filtering and concentrating thesolution in a water-jet vacuum and drying in vacuo, 11.54 g of crudeproduct were obtained in the form of a tacky oil.

Yield: 13.5% [concentration (HPLC) 16.8%].

Example 22 Methyl4-(4-fluorophenyl)-6-isopropyl-2-(N-methanesulphonyl-N-methylamino)pyrimidine-5-carboxylate

Ib, R¹=R²=R³=Methyl, R⁴=Isopropyl, TiCl₄, Chlorobenzene

10.0 g (37.7 mmol) of methyl2-[1-amino-1-(4-fluorophenyl)methylene]-4-methyl-3-oxopentanoate wereintroduced into 50 ml of chlorobenzene together with 5.08 g (37.7 mmol)of N-cyano-N-methylmethanesulphonamide and the mixture was treated atroom temperature with 7.22 g (37.7 mmol) of titanium tetrachloride. Thereaction progressed exothermically. The red-orange-coloured suspensionwas heated to 110-120° C. and stirred for 5 h. It was then cooled toroom temperature and treated with 30 ml of water. The organic phase wasseparated off and the aqueous phase was extracted with methylenechloride (2×30 ml). The combined organic phases were washed with 30 mlof water and dried over magnesium sulphate. After filtering andconcentrating the solution in a water-jet vacuum and drying in vacuo,12.02 g of crude product were obtained in the form of a tacky oil.

Yield: 15.0% [concentration (HPLC) 17.9%].

Example 23 Methyl3-amino-2-[1-(4-fluorophenyl)methanoyl]-4-methylpent-2-enoate

VI, R³=R⁴=Methyl

5.00 g of methyl 4-fluorobenzoylacetate (24.2 mmol, concentration 95%)and 1.69 g of isobutyronitrile (24.2 mmol, concentration 98%) weredissolved in 25 ml of toluene and treated with 7.01 g of tintetrachloride (26.6 mmol, concentration >99%) at room temperature afterthe course of 10 minutes. After 3 h at room temperature, the mixture washeated to 80° C. After 11.5 h, the suspension was again cooled to roomtemperature and treated with 25 ml of water. The mixture was dilutedwith 10 ml of ethyl acetate and the phases were separated. The organicphase was washed twice with 10 ml of 1N sodium hydroxide solution andconcentrated in vacuo (40° C./25 mbar) after drying over magnesiumsulphate. 6.18 g of crude product were obtained in the form of a yellowoil. After chromatography on silica gel (eluent: hexane/ethyl acetate1.5:1), 3.84 g of methyl3-amino-2-[1-(4-fluorophenyl)methanoyl]-4-methylpent-2-enoate wereobtained in the form of an oil.

Yield: 59.0%; concentration (HPLC): 98.6%.

GC-MS: M⁺=265. 0

¹H NMR (CDCl₃, 400 MHz): δ=0.98 (d); 1.25 (d); 2.90 (sept); 3.34 (s);3.47 (s); 3.52 (sept); 5.50 (s, broad); 5.90 (s, broad); 7.08 (m); 7.50(dd); 7.85 (dd); 9.04 (s, broad); 10.86 (s, broad).

¹³C NMR (CDCl₃, 100 MHz): δ=20.68 (q); 20.76 (q); 30.58 (d); 30.78 (d);50.57 (q); 51.17 (q); 96.86 (s); 101.09 (s); 114.85 (d); 115.06 (d);115.16 (d); 115.37 (d); 128.67 (d); 128.76 (d); 131.33 (d); 131.42 (d);136.98 (s); 137.01 (s); 139.37 (s); 139.40 (s); 162.48 (s); 164.04 (s);164.95 (s); 166.56 (s); 169.33 (s); 170.33 (s); 171.58 (s); 175.91 (s);193.24 (s); 194.40 (s).

Example 24 Methyl3-amino-2-[1-(4-fluorophenyl)methanoyl]-4-methyl-pent-2-enoate

VI, R³=R⁴=Methyl

39.2 g of methyl 4-fluorobenzoylacetate (0.20 mmol) and 16.8 g ofisobutyronitrile (0.24 mol, concentration >99%) were dissolved in 200 mlof toluene and treated with 57.9 g of tin tetrachloride (0.22 mmol,concentration >99%) at room temperature after the course of 10 minutes.After 30 min at room temperature, the mixture was heated to 80° C. After8 h, the suspension was again cooled to room temperature and treatedwith 200 ml of water. The mixture was diluted with 200 ml of ethylacetate and the phases were separated. The organic phase was washedtwice with 40 ml of 1N sodium hydroxide solution and concentrated invacuo (40° C./25 mbar) after drying over magnesium sulphate. 50.9 g ofcrude product were obtained in the form of a yellow oil. Afterchromatography of 12.0 g of crude product on silica gel (eluent:hexane/isopropanol 90:10), 10.08 g of methyl3-amino-2-[1-(4-fluoro-phenyl)methanoyl]-4-methylpent-2-enoate wereobtained in the form of a yellowish oil.

Yield: 86.3%; (concentration: >99%).

Example 25 Methyl4-(4-fluorophenyl)-6-isopropyl-2-(N-methanesulphonyl-N-methylamino)pyrimidine-5-carboxylate

Ib, R¹=R²=R³=Methyl, R⁴=Isopropyl

2.65 g (10.0 mmol) of methyl3-amino-2-[1-(4-fluorophenyl)methanoyl]-4-methylpent-2-enoate wereintroduced into 5.52 g (50.0 mmol) of N-methylmethanesulphonamide and1.48 g (20.0 mmol) of tert-butanol. 4.95 g (50.0 mmol) of sodiumtert-butoxide were added to this solution after the course of 2 minbetween 23 and 52° C. A yellowish, thick suspension was formed. After 1h, 2.00 g (32.5 mmol) of cyanogen chloride gas were introduced at 25° C.after the course of 20 min. The suspension, which was now more readilystirrable, was stirred for 18 h at 60° C. The reaction mixture waspoured onto water (20 ml). The resulting solid was filtered off andwashed with water (2×5 ml). After drying in a high vacuum, 740 mg ofcrude product were obtained in the form of a beige solid having aconcentration of 70.0% (HPLC). This corresponded to a yield of 13.6% ofmethyl4-(4-fluorophenyl)-6-isopropyl-2-(N-methanesulphonyl-N-methylamino)pyrimidine-5-carboxylate.

Example 26 Methyl4-(4-fluorophenyl)-6-isopropyl-2-(N-methanesulphonyl-N-methylamino)pyrimidine-5-carboxylate

Ib, R¹=R²=R³=Methyl, R⁴=Isopropyl

2.50 g (9.42 mmol) of methyl3-amino-2-[1-(4-fluorophenyl)methanoyl]-4-methylpent-2-enoate wereintroduced into 2.08 g (28.3 mmol) of N-methylmethanesulphonamide and3.49 g (47.1 mmol) of tert-butanol together with 3.79 g (28.3 mmol) ofN-cyano-N-methylmethanesulphonamide. 1.87 g (18.8 mmol) of sodiumtert-butoxide were added to this suspension at room temperature afterthe course of 15 min (exothermic). After 4 h at 76° C., the reactionsuspension was poured onto 20 g of ice water. The suspension was stirredin an ice bath, and the precipitate was filtered off and washed withwater (2×2.5 ml). After drying in a high vacuum, 1.61 g of methyl4-(4-fluorophenyl)-6-isopropyl-2-(N-methanesulphonyl-N-methylamino)pyrimidine-5-carboxylatewere obtained in the form of a pale beige solid.

Yield: 9.8%; concentration (HPLC): 21.9%.

Example 27 Methyl4-(4-fluorophenyl)-6-isopropyl-2-(N-methanesulphonyl-N-methylamino)pyrimidine-5-carboxylate

Ib, R¹=R²=R³=Methyl, R⁴=Isopropyl, Sodium Tert-butoxide, Compound of theFormula IVb Formed in situ

132.6 g (0.50 mol) of methyl2-[1-amino-1-(4-fluorophenyl)methylene]-4-methyl-3-oxopentanoate wereintroduced into 276.2 g (2.50 mol) of N-methylmethanesulphonamide and74.1 g (1.00 mol) of tert-butanol. 243.7 g (2.50 mol) of sodiumtert-butoxide were added to this suspension at 30° C. in portions suchthat the temperature did not rise above 60° C. A yellowish, thicksuspension was formed. After 20 min at 28° C., the mixture was heated to50° C. and 100.0 g (1.63 mol) of cyanogen chloride gas were introducedafter the course of 1 h. The suspension, which was now more readilystirrable, was stirred at 60° C. for 19.5 h. The reaction mixture waspoured onto water (750 ml) and stirred at room temperature for 15 min.The resulting solid was filtered off and washed with 2×250 ml of waterand 2×200 ml of cold methanol. After drying in a high vacuum, 119.1 g ofcrude product were obtained in the form of a beige solid having aconcentration of 90.1% (HPLC). This corresponded to a yield of 56.3% ofmethyl4-(4-fluorophenyl)-6-isopropyl-2-(N-methanesulphonyl-N-methylamino)pyrimidine-5-carboxylate.

Example 28 Methyl4-(4-fluorophenyl)-6-isopropyl-2-(N-methanesulphonyl-N-methylamino)pyrimidine-5-carboxylate

Ib, R¹=R²=R³=Methyl, R⁴=Isopropyl, NaOtBu, MMSA, CMMSA

2.97 g (11.2 mmol) of methyl2-[1-amino-1-(4-fluorophenyl)methylene]-4-methyl-3-oxopentanoate wereintroduced into 2.45 g (22.4 mmol) of N-methyl-methanesulphonamide(MMSA) and 4.19 g (55.9 mmol) of tert-butanol together with 4.51 g (36.6mmol) of N-cyano-N-methylmethanesulphonamide (CMMSA). 2.22 g (22.4 mmol)of sodium tert-butoxide were added to this suspension at roomtemperature in portions. An orange-coloured suspension was obtained. Itwas heated to 50° C. and stirred at 50° C. for 19.9 h. The suspensionwas poured onto 20 g of ice water, and the precipitate was filtered offand washed with water (2×5 ml). After drying in a high vacuum, 2.91 g ofmethyl4-(4-fluoro-phenyl)-6-isopropyl-2-(N-methanesulphonyl-N-methyl-amino)pyrimidine-5-carboxylatewere obtained in the form of a pale beige solid having a concentrationof 76.4% (HPLC), which corresponds to a yield of 52.1%.

What is claimed is:
 1. A process for the preparation of a compound ofthe formula:

In which R is hydrogen or a group of the formula —SO₂R¹; R¹ isC₁₋₆-alkyl; R² is hydrogen or C₁₋₆-alkyl; R³ is C₁₋₆-alkyl; and R⁴ isC₁₋₆-alkyl, comprising in a first stage, reacting a compound of theformula:

in which R³ and R⁴ have the above-mentioned meanings, in the presence ofa Lewis acid with 4-fluorobenzonitrile to give a compound of theformula:

in which R³ and R⁴ have the above-mentioned meaning, and, in a secondstage, reacting the compound of the formula III with a compound of theformula:

in which R and R² have the above-mentioned meanings, to give the finalproduct of the formula I.
 2. The process according to claim 1, wherein Rand R² are hydrogen, R⁴ is isopropyl and R³ is C₁₋₆-alkyl.
 3. Theprocess according to claim 2, wherein R³ is methyl.
 4. The processaccording to claim 1, wherein the Lewis acid employed in the first stageis tin tetrachloride.
 5. The process according to claim 4, wherein thefirst stage is carried out in the presence of an organic solvent.
 6. Theprocess according to claim 5, wherein the first stage is carried out ata temperature from −5 to 140° C.
 7. The process according to claim 6,wherein the second stage is carried out in the presence of an organicsolvent, a mixture of water with an organic solvent or in water.
 8. Theprocess according to claim 7, wherein the reaction in the second stageis carried out at a temperature from 10 to 120° C.
 9. The processaccording to claim 1, wherein the Lewis acid employed in the first stageis tin tetrachloride.
 10. The process according to claim 1, wherein thefirst stage is carried out in the presence of an organic solvent. 11.The process according to claim 1, wherein the reaction in the firststage is carried out at a temperature from −5 to 140° C.
 12. The processaccording to claim 1, wherein the second stage is carried out in thepresence of an organic solvent, a mixture of water with an organicsolvent or in water.
 13. The process according to claim 1, wherein thereaction in the second stage is carried out at a temperature from 10 to120° C.
 14. The process according to claim 8, wherein the compound ofthe formula III is isolated by extraction from reaction mixture of thefirst stage, and then reacted in the reaction of the second stage. 15.The process according to claim 1, wherein the compound of the formulaIII is isolated by extraction from the reaction mixture of the firststage, and then reacted in the reaction of the second stage.